Approach to phenanthroindolizidine alkaloids using organic azides with 1- Aryl allylic alcohols: Unexpected tandem reactions to indenyl aziridines via nazarov cyclization

Article abstract of DOI:10.3987/COM-16-13489

Organic azide cyclization reactions with 1- Aryl allylic alcohols were investigated in a synthetic study of phenanthroindolizidine alkaloids. Unsaturated imines (enimines) were effectively obtained from the allylic alcohol adjacent to electron-rich aromat

Full text of DOI:10.3987/COM-16-13489

HETEROCYCLES, Vol. 92, No. 7, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 22nd April, 2016, Accepted, 18th May, 2016, Published online, 25th May, 2016
DOI: 10.3987/COM-16-13489
APPROACH TO PHENANTHROINDOLIZIDINE ALKALOIDS USING
ORGANIC
AZIDES
WITH
1-ARYL ALLYLIC ALCOHOLS:
UNEXPECTED TAMDEM REACTIONS TO INDENYL AZIRIDINES VIA
NAZAROV CYCLIZATION
Taiki Yokoi, Takahiro Sugiura, Hiroki Tanimoto,* Tsumoru Morimoto,
Yasuhiro Nishiyama, and Kiyomi Kakiuchi
Graduate School of Materials Science, Nara Institute of Science and Technology
(NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; E-mail:
tanimoto@ms.naist.jp
Abstract – Organic azide cyclization reactions with 1-aryl allylic alcohols were
investigated in a synthetic study of phenanthroindolizidine alkaloids. Unsaturated
imines (enimines) were effectively obtained from the allylic alcohol adjacent to
electron-rich aromatic rings under thermal reaction conditions. The tandem
aziridination-Nazarov reactions to indenyl aziridines were preferred to the
acid-mediated enimine formation via Schmidt reaction in the case of 3-aryl
diallylic alcohols.
α,β-Unsaturated imines (1-aza-1,3-butadienes, or enimines) and related compounds (like the
corresponding oximes) are synthetically useful and show characteristic bioactivity.1,2 These compounds
can function as hetero-Diels-Alder dienes, dienophiles, and Michael acceptors. However, their use in
organic synthesis is limited due to the tendency toward polymerization and hydrolysis resulting from high
reactivity. Previously, we have developed a novel enimine synthesis from allylic alcohols and organic
azides utilizing the allylic cation-mediated Schmidt reaction.3 Our method was successfully used in the
total syntheses of unstable α,β- and α,β,γ,δ-unsaturated imine Costa Rican ant venom alkaloids (Scheme
1). To further develop our methodology, approaches to more complex natural products should be
examined, and we chose tylophorine and antofine as our synthetic targets. Tylophorine and antofine of the
phenanthroindolizidine alkaloid family are known to exhibit anticancer activity and have attracted
attention as synthetic targets for new and challenging strategies.4,5 Herein, we report our approach
utilizing the reactions of organic azides, and describe unexpected tandem aziridination-Nazarov
cyclization reactions affording indenyl aziridines.

acidic conditions
(low temperature)
R
R
N
R
OP
N
N3
A,B-unsaturated imines (enimines)
(enoximes, R = OR')
R = alkyl, Ph
P = H, protecting groups
efficient synthons toward bioactive
heterocycles and natural products
OMe
MeO
H
N
C–C bond: R = OMe (–)-tylophorine
R = H (–)-antofine
no C–C bond: R = OMe (–)-septicine
MeO
R
Scheme 1. Synthesis of unsaturated imines (enimines) from organic azides
Two retrosynthetic approaches for construction of the indolizidine alkaloid core are presented in Scheme
2. The first approach relies on the aza-[4+2] cycloaddition of enimine 2 with arylacetylene or styrene
derivatives, which can be obtained from the 1-aryl allylic alcohol 3 using the developed enimine
synthesis.3 The second route involves 6π-electrocyclization of the α,β,γ,δ-unsaturated imine 4, which
could be similarly obtained from diallylic alcohol 5. Compounds 3 and 5 could be prepared from the
commercially available 3,4-dimethoxybenzaldehyde. In both routes, the electron-rich dimethoxyphenyl
group was set at the β-carbon of enimines.
Scheme 2. Retrosynthetic routes to tylophorine and septicine
The first approach using the hetero-[4+2] cycloaddition started with the reaction of
3,4-dimethoxybenzaldehyde with tosyloxypentyne 6,3a followed by protection of the alcohol with a
methoxymethyl (MOM) group (Scheme 3). At this stage, the product partially reacted with chloride from
MOMCl via an SN2 substitution reaction to afford 7, which was obtained in excellent yield by addition of
tetrabutylammonium chloride. Reduction of the alkyne moiety using Lindlar’s catalyst was followed by

azidation to yield the cyclization precursor 8. When the hydroxy group was not protected, a
1,3-rearrangement to cinnamyl alcohol occurred under the reduction conditions. Next, we investigated the
azide-allyl ether cyclization to enimine 2. Although 1-phenyl allylic alcohol has previously been reported
to afford the corresponding enimines,3a,c the typical conditions using TMSOTf or BF3·OEt2 did not give
the desired product, probably due to the instability of the substrate under acidic conditions, imparted by
the electron-rich dimethoxyphenyl group. When trifluoroacetic acid was used, 2 was obtained in 29%
yield. Therefore, thermal cyclization conditions were tested, which were previously reported to be not
effective.3a,c Under these conditions, 2 was successfully obtained in 79% yield over three steps.
With the [4+2] cyclization precursor in hand, we examined hetero-[4+2] cyclizations. The initially
attempted reaction with acrylonitrile and methyl enol ether derivatives in the presence or absence of
Lewis acids did not occur. Following Yoshikai’s6 and Ellman’s7 procedures using cobalt or rhodium
catalysts, cyclizations with arylalkyne 98 to afford 10 were investigated. However, the starting material 2
was still unreactive. It should be noted that although typical enimines are unstable enough to decompose
in 2–3 days, 2 was a bench stable crystalline compound with its structure confirmed by X-ray analysis.
Thus, dienophiles for 2 were considered to be considerably more unreactive than typical enimines. We
also tested organocatalytic [4+2] reactions with enal 11 (LUMO activation) and homobenzaldehyde 12
(HOMO activation).9,10 Disappointingly, although the starting material was consumed, only trace amounts
of aza-Michael addition or condensation products were observed.
1)
OTs
6
Ar
Cl
n-BuLi, THF, –78 °C
1) H2, Lindlar's cat., AcOEt, 96%
3,4-dimethoxy-
benzaldehyde
N3
Ar
2) MOMCl, i-Pr2NEt
n-Bu4NCl, CH2Cl2
MOMO
2) NaN3, DMF, 50 °C, 94%
7
OMOM
8
reflux, 99% (for 2 steps)
Ar = 3,4-dimethoxyphenyl
Ar
Ar
a) TFA, CH2Cl2
0 °C, 29%
9
TMS
Ar
N
Ar
b) toluene, 120 °C
79% for 3 steps from 7
N
[RhCl(COD)]2
or
CoBr2/P(3-ClC6H4)3
TMS
10
2
CHO
Ar
Ar
CHO
Ar
Ar
or
11
12
or
N
N
OHC
Ar
Ph
Ph
OTMS
Ar
OH
14
ORTEP figure of 2
15
N
H
13
Scheme 3. Synthesis of enimine 2 and related hetero-[4+2] cyclization reaction approaches
Therefore, we directed our efforts to the 6π-electrocyclization reaction (Scheme 4). The propargyl ketone
16 obtained from 3,4-dimethoxybenzaldehyde was reacted with the lithiated vinyl bromide 18 to afford

alcohol 17. The alkyne moiety was reduced to olefin, and subsequent azidation afforded the cyclization
precursor 5.
Scheme 4. Synthesis of the diallylic alcohol 5 possessing an azido group
Based on the results of the conversion from 8 to 2, a cyclization reaction under heating conditions was
initially attempted with 5 (Scheme 5). Although all of the starting material was consumed, the only
product obtained in good yield was the enone 20, with no α,β,γ,δ-unsaturated imine 4 detected. This
unexpected reaction is presumably explained by the retro-aldol transformation of the intermediate
β-hydroxylimine 19,3a accelerated by the electron donating aromatic group.
Scheme 5. Attempted cyclization of 5 under thermal conditions
Considering the above results, we switched back to acid-mediated conversion. After the investigation of
reaction conditions, TMSOTf was found to give reproducible results. However, instead of the desired
dienimine 4, the reaction yielded the indenyl aziridine 24 in moderate yield (Scheme 6). The structure of
24 was unambiguously determined by X-ray crystallographic analysis (Figure 1).
A plausible mechanism is depicted in Scheme 6. After generation of the 1-pheny allylic cation by
TMSOTf, a cyclization reaction with the azido moiety followed, to give the aminodiazonium intermediate
21. In our previous study,3a,c including the case of 1-aryl allylic alcohol, the last step of the Schmidt
reactions involved the loss of a proton11 and nitrogen gas. However, in this case, the electron-rich
dimethoxyphenyl group could induce a reaction with the diazonium moiety of 21 to afford triazoline 2212
prior to proton loss.13 This is probably one of the reasons for the low yield and irreproducibility of the
transformation of 8 to 2 under acidic conditions (Scheme 3), since the acid-labile triazoline structure

would be immediately decomposed to aziridine.3a,12 Finally, Nazarov cyclization of the generated 1-aryl
allylic cation 23 produced indene 24.14 The Nazarov reaction and aziridine formation could be performed
independently.
Scheme 6. Tandem transformation of the azido diallylic alcohol 5 to indenyl aziridine 24
Figure 1. ORTEP figure of the indenyl aziridine 24
In our previous study, a 1-phenyl allylic alcohol was successfully converted to the desired enimine. A
model study to investigate the previously unobserved tandem reaction was set up (Scheme 7). Although
product 26 was obtained in lower yield than 24 in Scheme 6, the tandem reaction occurred in the absence
of electron-donating groups in the upper benzene ring. However, without an aromatic ring on the bottom
side, the expected product 28 was not formed. These results indicate that the presence of aromatic
moieties or electron-donating groups can strongly influence the aziridination-Nazarov reaction.
In conclusion, we investigated the cyclization reactions of organic azides and the influence of
electron-rich benzene rings in a synthetic study of indolizidine alkaloids. In the case of a secondary
benzyl alcohol, thermal reaction conditions were effective for obtaining the unsaturated imine. In the

presence of an electron-rich group, triazoline formation followed by aziridination was preferred to
acid-mediated enimine formation via the Schmidt reaction. These results should facilitate the
development of Schmidt reactions and an understanding of the behavior of organic azides. Further
applications of the discovered reactions and the synthetic approach to alkaloids will follow in due course.
Scheme 7. Model study of tandem aziridination/Nazarov reaction
EXPERIMENTAL
General Information: 1H and 13C NMR spectra were recorded using a JEOL JNM-ECP500 spectrometer
(500 MHz for 1H NMR and 126 MHz for 13C NMR). Chemical shifts are reported as δ values in ppm and
1
13
calibrated with respect to the residual solvent peak (CDCl3: δ 7.26 for H NMR and δ 77.00 for C
1
NMR) or tetramethylsilane (δ 0 for H NMR). The abbreviations used are as follows: s (singlet), d
(doublet), t (triplet), q (quartet), br (broad), m (complex multiplet). Melting points were measured using a
Yanaco Micro melting point apparatus. Infrared spectra were measured using a Jasco FT-IR-4200
spectrometer. Mass spectra were recorded using a Jeol JMS-700 MStaion [EI (70 eV), CI, FAB, and ESI].
Flash column chromatography was performed using Merck Silica gel 60. The progress of the reactions
was monitored by silica gel thin layer chromatography (TLC) (Merck TLC Silica gel 60 F254). The further
purifications of the crude materials were performed using a LC-908 recycling gel permeation
chromatography (GPC) equipped with a JAIGEL 2H-40 column (CHCl3 elution) made by Japan
Analytical Industry Co., Ltd. Phosphomolybdic acid was used for the TLC stains, and TLC was also
monitored with UV lamp. All the reagents were purchased from Sigma-Aldrich, Wako Pure Chemical
Industries, Ltd, TCI (Tokyo Chemical Industry, Co. Ltd), Kanto Chemical Co. Inc., and Nakalai Tesque.
Anhydrous tetrahydrofuran (THF) was purchased from Kanto Chemical.
4-(6-Chloro-1-(methoxymethoxy)hex-2-yn-1-yl)-1,2-dimethoxybenzene (7): To a stirred solution of
alkyne 6 (3.59 g, 15.1 mmol)3a in THF (45 mL) was added n-butyllithium (hexane solution, 10. mL, 1.63
M, 16.5 mmol) at -78 °C. After 14 min, 3,4-dimethoxybenzaldehyde (1.66 g, 10.0 mmol) dissolved in
THF (40mL) was added to the mixture dropwise. After 2 h, saturated ammonium chloride aqueous

solution was added to stop the reaction. The mixture was extracted with EtOAc, and the extract was
washed with water and brine. Drying collected organic layer was concentrated in vacuo to afford crude
material (4.05 g) which was submitted to the next reaction without further purification due to the
instability of the product.
To the stirred solution of the crude material (4.05g) in CH2Cl2 (100 mL) was added tetrabutylammonium
chloride (6.63 g, 17.9 mmol), and the mixture was cooled to 0 °C. To the mixture were added
diisopropylethylamine (5.2 mL, 30 mmol) and chloromethyl methyl ether (1.5 mL, 20 mmol)
successively, and the mixture was stirred at room temperature for 18 h. Additional diisopropylethylamine
(1.74 mL, 10.0 mmol) and chloromethyl methyl ether (0.75 mL, 9.9 mmol) were added, and the mixture
was stirred at room temperature for 5 h, then heated at 50 °C for 3 h. The reaction mixture was extracted
with CH2Cl2, and the extract was washed with water and brine. Drying collected organic layer followed
by silica gel column chromatography (hexane/EtOAc = 5/1 to 2/1) to afford 7 (3.08 g, 99% for 2 steps).
Colorless oil; Rf value 0.47 (hexane/EtOAc = 2/1); IR (NaCl, neat) νmax 2951, 1516, 1260, 1234, 1146,
1027 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.06 (d, 1H, J = 1.5 Hz), 7.02 (dd, 1H, J = 8.0, 2.0 Hz), 6.85 (d,
1H, J = 8.0 Hz), 5.33 (br-s, 1H), 4.96 (d, 1H, J = 7.0 Hz), 4.62 (d, 1H, J = 7.0 Hz), 3.91 (s, 3H), 3.89 (s,
3H), 3.65 (t, 2H, J = 6.5 Hz), 3.42 (s, 3H), 2.49 (dt, 2H, J = 7.0, 2.5 Hz), 1.99 (tt, 2H, J = 7.0, 6.5 Hz); 13C
NMR (126 MHz, CDCl3) δ 149.13, 149.05, 131.4, 120.0, 110.7, 110.4, 93.6, 85.8, 79.0, 67.3, 55.9, 55.8,
55.7, 43.6, 31.2, 16.3; HRMS (ESI) calcd for C16H21ClO4Na [(M+Na)+] 335.1026, found 335.1022.
Synthesis of (E)-5-(3,4-dimethoxystyryl)-3,4-dihydro-2H-pyrrole (2) by three-step sequence: To a
stirred solution of 7 (2.86 g, 9.2 mmol) in EtOAc (91 mL) was added Lindlar’s catalyst (286.6 mg). The
atmosphere in the flask was replaced to hydrogen under balloon pressure, and the reaction mixture was
vigorously stirred. After 26 h, the mixture was filtered through a pad of Celite to afford crude material of
(Z)-4-(6-chloro-1-(methoxymethoxy)hex-2-en-1-yl)-1,2-dimethoxybenzene (2.88 g, 96%) which was
submitted to the next reaction without further purification.
Analytical data of (Z)-4-(6-chloro-1-(methoxymethoxy)hex-2-en-1-yl)-1,2-dimethoxybenzene:
Further purification was not necessary to collect analytical data. Colorless oil; Rf value 0.70
(hexane/EtOAc = 1/1); IR (NaCl, neat) νmax 3000, 2934, 2839, 1515, 1464, 1261, 1145, 1094, 1028 cm-1;
1H NMR (500 MHz, CDCl3) δ 6.92 (s, 1H), 6.91 (dd, 1H, J = 8.5, 1.5 Hz), 6.83 (d, 1H, J = 8.5 Hz), 5.66
(m, 1H), 5.57 (m, 1H), 5.40 (d, 1H, J = 9.0 Hz), 4.68 (d, 1H, J = 7.0 Hz), 4.59 (d, 1H, J = 7.0 Hz), 3.89 (s,
3H), 3.87 (s, 3H), 3.54 (m, 2H), 3.39 (s, 3H), 2.37 (td, 2H, J = 7.5, 7.5 Hz), 1.86 (m, 2H); 13C NMR (126
MHz, CDCl3) δ 149.0, 148.4, 133.8, 131.3, 130.7, 119.1, 110.9, 109.6, 93.2, 72.1, 55.8, 55.8, 55.4, 44.3,
32.1, 24.7; LRMS (EI) m/z 314 (43%), 255 (40), 253 (100), 241 (45); HRMS (EI) calcd for C16H23ClO4
(M+) 314.1285, found 314.1287.

To a stirred solution of crude (Z)-4-(6-chloro-1-(methoxymethoxy)hex-2-en-1-yl)-1,2-dimethoxybenzene
(2.88 g) in DMF (92 mL) was added sodium azide (777 mg, 12.0 mmol), and the mixture was heated to
50 °C. After 20 h, the mixture was extracted with Et2O and the extract was washed with water and brine.
Drying collected organic layer followed by concentration in vacuo afforded crude 8 (2.55 g) which was
submitted to the next reaction without further purification. When purified, silica gel column
chromatography (hexane/EtOAc = 5/1) afforded 8 (125.7 mg, 94%).
Analytical data of (Z)-4-(6-azido-1-(methoxymethoxy)hex-2-en-1-yl)-1,2-dimethoxybenzene (8):
Colorless oil; Rf value 0.43 (hexane/EtOAc = 5/1×3); IR (NaCl, neat) νmax 2938, 2097, 1516, 1261, 1147,
1030 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.91 (m, 1H), 6.89 (d, 1H, J = 1.5 Hz), 6.83 (m, 1H), 5.65 (m,
1H), 5.58 (td, 1H, J = 11.0, 7.5 Hz), 5.37 (d, 1H, J = 9.0 Hz), 4.68 (d, 1H, J = 6.5 Hz), 4.58 (d, 1H, J =
6.0 Hz), 3.89 (s, 3H), 3.87 (s, 3H), 3.40 (s, 3H), 3.28 (dt, 2H, J = 7.0, 1.5 Hz), 2.33–2.24 (m, 2H), 1.73–
1.64 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 149.1, 148.5, 133.8, 131.04, 131.02, 119.2, 110.9, 109.6,
93.1, 72.1, 55.84, 55.79, 55.5, 50.7, 28.5, 24.7; HRMS (ESI) calcd for C16H23N3O4Na [(M+Na)+]
344.1586, found 344.1585.
To a stirred solution of crude 8 (2.55 g) in toluene (79 mL) was heated to 120 °C. After 16 h, the mixture
was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography
(hexane/EtOAc = 1/2 to CHCl3/MeOH = 15/1) to afford 2 (1.68 g, 79% for 3 steps).
Analytical data of (E)-5-(3,4-dimethoxystyryl)-3,4-dihydro-2H-pyrrole (2, CCDC 1474594): White
crystal; Rf value 0.39 (CH2Cl2/MeOH = 10/1); mp 119.3–120.6 °C; IR (NaCl, neat) νmax 2958, 2932, 1632,
1590, 1513, 1265, 1139, 1025 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.06 (d, 1H, J = 1.5 Hz), 7.04 (dd, 1H,
J = 8.0, 1.5 Hz), 7.00 (d, 1H, J = 16.5 Hz), 6.90 (d, 1H, J = 16.5 Hz), 6.86 (d, 1H, J = 8.0 Hz), 3.98 (t, 2H,
J = 7.5 Hz), 3.91 (s, 3H), 3.90 (s, 3H), 2.77 (t, 2H, J = 8.0 Hz), 1.97 (tt, 2H, J = 8.0, 7.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 173.9, 149.9, 149.1, 138.2, 129.0, 123.2, 121.1, 111.0, 108.8, 61.2, 55.9, 55.8, 33.4,
22.5; HRMS (ESI) calcd for C14H18NO2 [(M+H)+] 232.1338, found 232.1339.
Compound 8 from 2 by TFA-mediated reaction: To a stirred solution of 2 (17.4 mg, 54.1 μmol) in
CH2Cl2 (1 mL) was added trifluoroacetic acid (8 μL, 110 μmol) at 0 °C. After 1 h, the reaction was
quenched with saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with
EtOAc and washed with brine. Drying the collected organic layer over magnesium sulfate followed by
concentration in vacuo and silica gel column chromatography (hexane/EtOAc = 7/2 to 1/1) afforded 8
(3.6 mg, 29%).
6-(3,4-Dimethoxyphenyl)-6-oxohex-4-yn-1-yl 4-methylbenzenesulfonate (16): To a stirred solution of
6 (2.26 g, 9.5 mmol)3a in THF (48 mL) was added n-butyllithium (hexane solution, 6.7 mL, 1.55 M, 10.4
mmol) at -78 °C. After 14 min, 3,4-dimethoxybenzaldehyde (1.05 g, 6.3 mmol) in THF (15 mL) was
added dropwise at the same temperature. After 2 h, saturated ammonium chloride aqueous solution was

added to the mixture. The mixture was extracted with EtOAc, and was washed with water and brine.
Drying collected organic layer over sodium sulfate followed by silica gel column chromatography
(hexane/EtOAc = 2/1 to 1/1) afforded propargyl alcohol (2.49 g, 98%). The product was submitted to the
next reaction due to the instability of the product.
To a vigorously stirred solution of the propargyl alcohol (2.47 g, 6.1 mmol) in CH2Cl2 (20 mL) was
added manganese dioxide (2.13 g, 24.5 mmol) at room temperature. After 24 h, the mixture was filtrated
through Celite. The obtained filtrate was concentrated in vacuo followed by silica gel column
chromatography (hexane/EtOAc = 2/1 to 3/2) to afford 16 (2.28 g, 93%). Yellow oil; Rf value 0.17
1
(hexane/EtOAc = 2/1); IR (NaCl, neat) νmax 1633, 1594, 1582, 1513, 1271, 1175 cm-1; H NMR (500
MHz, CDCl3) δ 7.78–7.76 (m, 3H), 7.55 (d, 1H, J = 2.0 Hz), 7.29 (d, 2H, J = 8.5 Hz), 6.92 (d, 1H, J = 8.5
Hz), 4.19 (t, 2H, J = 6.0 Hz), 3.96 (s, 3H), 3.93 (s, 3H), 2.58 (t, 2H, J = 6.0 Hz), 2.37 (s, 3H), 2.00 (tt, 2H,
J = 6.0 Hz); 13C NMR (126 MHz, CDCl3) δ 176.5, 154.3, 148.9, 145.0, 132.5, 130.1, 129.9, 127.8, 125.9,
110.0, 109.9, 92.6, 80.1, 68.4, 56.1, 56.0, 27.1, 21.6, 15.5; HRMS (ESI) calcd for C21H22O6SNa
[(M+Na)+] 425.1035, found 425.1035.
Preparation
of
1-bromo-1-(3,4-dimethoxyphenyl)ethene
(18):
To
a
stirred
3,4-dimethoxy-1-ethynylbenzene (713 mg, 4.4 mmol)8 was added acetic acid (1 mL) and hydrogen
bromide (acetic acid solution, 0.86 mL, 5.1 M, 4.4 mmol) successively. After 30 min, saturated sodium
hydrogen carbonate aqueous solution was added to the mixture at 0 °C. The mixture was extracted with
CH2Cl2, and the extract was washed with water and brine. Drying collected organic layer followed by
silica gel column chromatography (hexane/EtOAc = 15/1 to 5/1) to afford 18 (984 mg, 92%) as a pale
orange oil, which was soon submitted to the appropriate reactions due to its instability.
6,7-Bis(3,4-dimethoxyphenyl)-6-hydroxyoct-7-en-4-yn-1-yl 4-methylbenzenesulfonate (17): To a
stirred solution of n-butlyllithium (hexane solution, 0.12 mL, 1.55 M, 0.19 mmol) in THF (0.3 mL) was
added vinyl bromide 18 at -78 °C. After 20 min, 16 (50.7 mg, 0.13 mmol) dissolved in THF (0.5 mL) was
added dropwise to the reaction mixture at the same temperature. After 3 h, satulated ammonium chloride
aqueous solution was added. The mixture was extracted with EtOAc, and was washed with water and
brine. Drying collected organic layer over MgSO4 followed by silica gel column chromatography
(hexane/EtOAc = 3/1 to 2/1) afforded 17 (38.6 mg, 54%). Pale yellow gum; Rf value 0.33 (hexane/EtOAc
= 1/1); IR (NaCl, neat) νmax 1935, 1653, 1514, 1262, 1142, 1024 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.75
(d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.16 (dd, 1H, J = 8.0, 2.0 Hz), 7.11 (d, 1H, J = 1.5 Hz), 6.81
(d, 1H, J = 8.5 Hz), 6.70–6.67 (m, 2H), 6.60 (d, 1H, J = 1.0 Hz), 5.75 (d, 1H, J = 1.0 Hz), 5.31 (d, 1H, J =
1.0 Hz), 4.06 (t, 2H, J = 5.5 Hz), 3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.67 (s, 3H), 2.64 (s, 1H), 2.42 (s,
3H), 2.36 (t, 2H, J = 6.5 Hz), 1.81 (tt, 2H, J = 6.5, 6.0 Hz); 13C NMR (126 MHz, CDCl3) δ 151.3, 148.6,
148.6, 148.3, 147.7, 144.8, 135.4, 132.9, 131.7, 129.8, 127.8, 121.2, 118.9, 114.6, 112.0, 110.4, 110.2,

109.6, 86.0, 83.5, 74.8, 68.7, 55.9, 55.8, 55.7, 55.5, 27.8, 21.6, 15.2; HRMS (ESI) calcd for C31H34O8SNa
[(M+Na)+] 589.1872, found 589.1865.
(Z)-8-Azido-2,3-bis(3,4-dimethoxyphenyl)octa-1,4-dien-3-ol (5): To a stirred solution of 17 (763.0 mg,
1.4 mmol) in EtOAc (14 mL) was added Lindlar’s catalyst (764.1 mg). The atmosphere in the flask was
replaced to hydrogen under balloon pressure, and the reaction mixture was vigorously stirred. After 18 h,
the mixture was filtered through a pad of Celite to afford crude material of allyl alcohol (733 mg) which
was submitted to the next reaction due to the instability.
To a stirred solution of the allyl alcohol (733 mg) in DMF (13 mL) was added sodium azide (111.6 mg,
1.7 mmol). After 18 h, the mixture was extracted with Et2O, and the organic layer was washed with water
and brine. Drying collected organic layer over Na2SO4 followed by alumina column chromatography
(hexane/EtOAc = 3/1 to 2/1 to 1/1) afforded 5 (459.7 mg, 78% for 2 steps). Pale yellow oil; Rf value 0.57
1
(hexane/EtOAc = 1/1); IR (NaCl, neat) νmax 3508, 1095, 1513, 1254, 1141, 1027 cm-1; H NMR (500
MHz, CDCl3) δ 7.10 (s, 1H), 7.07 (d, 1H, J = 8.5 Hz), 6.84 (d, 1H, J = 8.5 Hz), 6.71 (d, 1H, J = 8.0 Hz),
6.67 (d, 1H, J = 8.5 Hz), 6.56 (s, 1H), 5.89 (d, 1H, J = 11.5 Hz), 5.56–5.50 (m, 2H), 5.32 (s, 1H), 3.88 (s,
3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.66 (s, 3H), 3.22 (t, 2H, J = 6.0 Hz), 2.39–2.26 (m, 2H), 1.63 (tt, 2H, J =
7.0, 6.5 Hz); 13C NMR (126 MHz, CDCl3) δ 153.7, 148.7, 148.3, 148.02, 147.97, 138.3, 135.3, 132.4,
120.9, 118.7, 114.9, 111.7, 110.5, 110.4, 109.7, 79.7, 55.82, 55.80, 55.7, 55.5, 50.9, 28.3, 25.7; HRMS
(ESI) calcd for C24H29N3O5Na [(M+Na)+] 462.2005, found 462.2006.
1,2-Bis(3,4-dimethoxyphenyl)prop-2-en-1-one (20): A stirred solution of 5 (5.6 mg, 0.013 mmol) in
o-xylene (1 mL) was heated to 120 °C. After 3 h, the mixture was concentrated in vacuo, and the residue
was purified by silica gel column chromatography (hexane/EtOAc = 3/1) to afford 20 (3.7 mg, 88%).
Colorless oil; Rf value 0.43 (hexane/EtOAc = 1/1); IR (NaCl, neat) νmax 2935, 2837, 1593, 1514, 1262,
1142, 1024 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.56 (d, 1H, J = 2.0 Hz), 7.52 (dd, 1H, J = 8.0, 1.5 Hz),
6.98 (d, 1H, J = 2.0 Hz), 6.95 (dd, 1H, J = 8.5, 2.5 Hz), 6.83 (t, 2H, J = 7.5 Hz), 5.92 (s, 1H), 5.47 (s, 1H),
3.93 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 196.6, 153.5, 149.3,
148.92, 148.89, 147.9, 130.0, 129.9, 125.7, 119.7, 117.3, 111.3, 111.0, 109.8, 109.6, 56.1, 56.0, 55.87,
55.85; HRMS (ESI) calcd for C19H20O5Na [(M+Na)+] 351.1208, found 351.1193.
6-(2-(3,4-Dimethoxyphenyl)-5,6-dimethoxy-1H-inden-3-yl)-1-azabicyclo[3.1.0]hexane (24, CCDC
1474595): To a stirred solution of 5 (7.4 mg, 0.017 mmol) in CH2Cl2 (1 mL) was added TMSOTf (6 μL,
0.034 mmol) at -78 °C. After 15 min, saturated sodium hydrogen carbonate aqueous solution was added
to the reaction mixture. The mixture was extracted with EtOAc and the organic layer was washed with
water and brine. Drying collected organic layer followed by silica gel column chromatography
(hexane/EtOAc = 1/1 to EtOAc elution) afforded 24 (4.7 mg, 71%). Pale yellow solid; Rf value 0.53
1
(CHCl3/MeOH = 15/1); mp 99.1–99.7 °C; IR (NaCl, neat) νmax 2936, 1514, 1488, 1238 cm-1; H NMR

(500 MHz, CDCl3) δ 7.34 (s, 1H), 7.05 (dd, 1H, J = 8.0, 2.0 Hz), 7.02 (d, 1H, J = 2.0 Hz), 7.01 (s, 1H),
6.91 (d, 1H, J = 8.0 Hz), 3.95 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.68 (d, 1H, J = 22.5 Hz),
3.59 (d, 1H, J = 22.5 Hz), 3.25 (br-dd, 1H, J = 12.0, 8.0 Hz), 3.08 (dt, 1H, J = 11.5, 7.0 Hz), 2.57 (s, 1H),
2.54 (dd, 1H, J = 5.5, 3.0 Hz), 2.25 (dd, 1H, J = 13.0, 8.5 Hz), 2.00 (m, 1H), 1.76 (m, 1H), 1.63 (m, 1H);
13C NMR (126 MHz, CDCl3) δ 148.5, 148.1, 148.0, 147.1, 141.3, 138.7, 135.0, 134.9, 130.0, 120.7, 111.5,
111.0, 107.4, 105.1, 56.2, 55.9, 53.3, 46.8, 41.1, 35.1, 26.3, 20.5; LRMS (EI) m/z 393 (M+, 29%), 165
(40), 149 (100), 57 (79); HRMS (EI) calcd for C24H27NO4 (M+) 393.1940, found 393.1923.
Preparation of model substrates 25 and 27:
6-Oxo-6-phenylhex-4-yn-1-yl 4-methylbenzenesulfonate: To a vigorously stirred solution of
6-hydroxy-6-phenyl-4-propyn-1-yl 4-toluenesulfonate (377 mg, 1.1 mmol)3a in CH2Cl2 (11 mL) was
added manganese dioxide (1.86 g, 21.7 mmol). After 12 h, the mixture was filtrated through Celite. The
obtained filtrate was concentrated in vacuo followed by silica gel column chromatography
(hexane/EtOAc = 3/1) to afford alkynyl ketone (262.5 mg, 70%). White solid; Rf value 0.3
1
(hexane/EtOAc = 3/1); mp 56–57 °C; IR (NaCl, neat) νmax 2238, 2204, 1643, 1266, 1175, 930 cm-1; H
NMR (500 MHz, CDCl3) δ 8.08–8.06 (m, 2H), 7.78 (d, 2H, J = 8.5 Hz), 7.62 (m, 1H), 7.50–7.47 (m, 2H),
7.28 (d, 2H, J = 7.0 Hz), 4.19 (t, 2H, J = 6.0 Hz), 2.60 (t, 2H, J = 7.0 Hz), 2.35 (s, 3H), 2.02 (tt, 2H, J =
7.5, 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 177.8, 145.0, 136.5, 134.1, 132.5, 129.9, 129.5, 128.6, 127.9,
93.5, 80.2, 68.3, 27.1, 21.6, 15.5; LRMS (EI) m/z 342 (M+, 100%), 170 (62), 141 (38); HRMS (EI) calcd
for C19H18O4S (M+) 342.0926, found 342.0920.
7-(3,4-Dimethoxyphenyl)-6-hydroxy-6-phenyloct-7-en-4-yn-1-yl 4-methylbenzenesulfonate: To a
stirred solution of n-butyllithium (hexane solution, 0.92 mL, 1.54 M, 1.4 mmol) in THF (1.2 mL) was
added THF solution (3 mL) of vinyl bromide 18 (318.4 mg, 1.3 mmol) was added dropwise at -78 °C.
After 20 min, 6-oxo-6-phenylhex-4-yn-1-yl 4-methylbenzenesulfonate (247.6 mg, 0.72 mmol) dissolved
in THF (3 mL) was added dropwise to the mixture. After 2 h, the reaction was stopped by addition of
saturated ammonium chloride aqueous solution. The mixture was extracted with EtOAc and was washed
with water and brine. Drying collected organic layer over MgSO4 followed by silica gel column
chromatography (hexane/EtOAc = 2/1 to 1/1) afforded the product (342.3 mg, 93%). Pale yellow oil; Rf
1
value 0.1 (hexane/EtOAc = 3/1); IR (NaCl, neat) νmax 3490, 1514, 1175, 1026, 930 cm-1; H NMR (500
MHz, CDCl3) δ 7.76 (d, 2H, J = 8.0 Hz), 7.59–7.57 (m, 2H), 7.34–7.26 (m, 5H), 6.72–6.67 (m, 2H), 6.48
(d, 1H, J = 2.0 Hz), 5.76 (d, 1H, J = 1.0 Hz), 5.31 (d, 1H, J = 1.0 Hz), 4.06 (t, 2H, J = 6.5 Hz), 3.81 (s,
3H), 3.61 (s, 3H), 2.64 (s, 1H), 2.42 (s, 3H), 2.36 (t, 2H, J = 7.0 Hz), 1.82 (tt, 2H, J = 7.0, 6.5 Hz); 13C
NMR (126 MHz, CDCl3) δ 151.2, 148.2, 147.6, 144.8, 142.9, 132.8, 131.6, 129.9, 128.1, 127.9, 127.8,
126.3, 121.2, 114.8, 111.8, 110.2, 86.2, 83.4, 68.8, 55.7, 55.4, 27.7, 21.6, 15.2; LRMS (EI) m/z 506 (M+,
9%), 343 (96), 163 (100); HRMS (EI) calcd for C29H30O6S (M+) 506.1763, found 506.1780.

(Z)-7-(3,4-Dimethoxyphenyl)-6-hydroxy-6-phenylocta-4,7-dien-1-yl 4-methylbenzenesulfonate: To a
stirred solution of 7-(3,4-dimethoxyphenyl)-6-hydroxy-6-phenyloct-7-en-4-yn-1-yl
4-methylbenzenesulfonate in EtOAc (6.8 mL) was added Lindlar’s catalyst (34.6 mg). The atmosphere in
the flask was replaced to hydrogen under balloon pressure. After 23 h, the mixture was filtered through a
pad of Celite and the filtrate was concentrated in vacuo followed by silica gel column chromatography
(EtOAc/hexane = 3/1) to afford the product (267.5 mg, 78%). Pale yellow amorphous solid; Rf value 0.47
1
(hexane/EtOAc = 3/1×3); IR (NaCl, neat) νmax 3519, 1514, 1357, 1252, 1175 cm-1; H NMR (500 MHz,
CDCl3) δ 7.75 (d, 2H, J = 8.0 Hz), 7.52–7.50 (m, 2H), 7.35–7.31 (m, 4H), 7.26 (m, 1H), 6.73–6.67 (m,
2H), 6.43 (d, 1H, J = 2.5 Hz), 5.88 (d, 1H, J = 11.5 Hz), 5.58 (m, 1H), 5.47 (d, 1H, J = 1.0 Hz), 5.30 (d,
1H, J = 1.0 Hz), 3.96 (m, 2H), 3.83 (s, 3H), 3.60 (s, 3H), 2.94 (s, 3H), 2.34–2.20 (m, 2H), 1.64 (m, 2H);
13C NMR (126 MHz, CDCl3) δ 153.5, 148.3, 147.9, 145.8, 144.6, 135.4, 133.0, 132.3, 132.2, 129.8, 128.2,
127.9, 127.1, 126.3, 121.0, 115.2, 111.5, 110.5, 79.9, 70.1, 55.7, 55.4, 28.5, 24.7, 21.6; HRMS (ESI)
calcd for C29H32O6SNa [(M+Na)+] 531.1817, found 531.1812.
(Z)-8-Azido-2-(3,4-dimethoxyphenyl)-3-phenylocta-1,4-dien-3-ol (25): To a stirred solution of
(Z)-7-(3,4-dimethoxyphenyl)-6-hydroxy-6-phenylocta-4,7-dien-1-yl 4-methylbenzenesulfonate (126.2 mg,
0.25 mmol) in DMF (2.5 mL) was added sodium azide (21.8 mg, 0.34 mmol), and the mixture was heated
at 50 °C. After 20 min, the mixture was extracted with Et2O and was washed with water and brine.
Drying collected organic layer over Na2SO4 followed by silica gel column chromatography
(hexane/EtOAc = 4/1) gave 25 (77.6 mg, 82%). Pale yellow oil; Rf value 0.37 (hexane/EtOAc = 3/1); IR
(NaCl, neat) νmax 3504, 2935, 2095, 1514, 1252, 1027 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.56–7.54 (m,
2H), 7.37–7.34 (m, 2H), 7.28 (m, 1H), 6.71 (m, 2H), 6.47 (d, 1H, J = 1.5 Hz), 5.97 (br-d, 1H, J = 12.0
Hz), 5.55 (td, 1H, J = 11.5, 7.0 Hz), 5.50 (d, 1H, J = 1.0 Hz), 5.32 (d, 1H, J = 1.0 Hz), 3.83 (s, 3H), 3.62
(s, 3H), 3.20 (t, 2H, J = 7.0 Hz), 2.41–2.27 (m, 2H), 1.62 (tt, 2H, J = 7.0, 6.5 Hz); 13C NMR (126 MHz,
CDCl3) δ 153.8, 148.3, 148.0, 145.9, 135.4, 132.6, 132.4, 128.2, 127.1, 126.4, 121.0, 115.2, 111.7, 110.5,
80.0, 55.7, 55.5, 50.9, 28.4, 25.8; HRMS (ESI) calcd for C22H25N3NaO3 [(M+Na)+] 402.1794, found
402.1795.
(Z)-6-Oxo-6-phenylhex-4-en-1-yl
4-methylbenzenesulfonate:
To
a
stirred solution
of
cis-6-azido-1-phenyl-2-propen-1-yl acetate (869.1 mg, 2.2 mmol)3a in CH2Cl2 (23 mL) was added
diisobutylaluminium hydride (toluene solution, 3.3 mL, 1.01 M, 3.4 mmol) at -78 °C. After 1 h, the
mixture was diluted with EtOAc followed by addition of saturated Rochell salt aqueous solution at room
temperature. After 2 h with vigorous stir, the mixture was extracted with EtOAc and was washed with
brine. Drying collected organic layer over Na2SO4 followed by silica gel column chromatography
(hexane/EtOAc = 2/1) afforded the allyl alcohol (697.1 mg, 73%), which was submitted to the next
reaction because of its instability.

To a vigorously stirred solution of the obtained allyl alcohol (659.1 mg, 1.9 mmol) in CH2Cl2 (19 mL)
was added manganese dioxide (3.30 g, 37.9 mmol) at room temperature. After 11 h, the mixture was
filtrated through Celite. The obtained filtrate was concentrated in vacuo followed by silica gel column
chromatography (hexane/EtOAc = 4/1) to afford the product (425.1 mg, 65%). Colorless oil; Rf value
1
0.37 (hexane/EtOAc = 3/1); IR (NaCl, neat) νmax 1665, 1359, 1230, 1175, 664, 554 cm-1; H NMR (500
MHz, CDCl3) δ 7.92–7.90 (m, 2H), 7.77 (d, 2H, J = 8.0 Hz), 7.56 (m, 1H), 7.48–7.45 (m, 2H), 7.31 (d,
2H, J = 8.0 Hz), 6.83 (td, 1H, J = 11.0, 2.0 Hz), 6.25 (dt, 1H, J = 11.5, 7.5 Hz), 4.07 (t, 2H, J = 6.5 Hz),
2.65 (dtd, 2H, J = 7.5, 7.0, 2.0 Hz), 2.42 (s, 3H), 1.87 (tt, 2H, J = 7.5, 7.0 Hz); 13C NMR (126 MHz,
CDCl3) δ 191.6, 146.9, 144.7, 138.2, 133.0, 132.9, 129.8, 128.6, 128.3, 127.9, 125.3, 70.0, 28.4, 25.8,
21.6; LRMS (EI) m/z 344 (M+, 23%), 172 (47), 105 (100), 91 (87), 77 (69); HRMS (EI) calcd for
C19H20O4S (M+) 344.1082, found 344.1091.
(Z)-8-Azido-3-phenylocta-1,4-dien-3-ol (27): To a stirred solution of (Z)-6-oxo-6-phenylhex-4-en-1-yl
4-methylbenzenesulfonate (328.7 mg, 0.95 mmol) in THF (9.5 mL) was added vinylmagnesium bromide
(THF solution, 3.8 mL, 1.0 M, 3.8 mmol) at -78 °C. After 1 h, saturated ammonium chloride aqueous
solution was added to the mixture. The mixture was extracted with EtOAc and was washed with brine.
Drying collected organic layer followed by silica gel column chromatography (hexane/EtOAc = 4/1)
afforded the product as an inseparable mixture (248.9 mg).
To the stirred solution of the mixture (248.9 mg, 0.63 mmol) in DMF (6.3 mL) was added sodium azide
(54.0 mg, 0.83 mmol), and the mixture was heated to 50 °C. After 40 min, the mixture was extracted with
Et2O, and was washed with water and brine. Drying collected organic layer followed by silica gel column
chromatography (hexane/EtOAc = 6/1) afforded 27 (94.7 mg, 41% for 2 steps). Pale yellow oil; Rf value
1
0.57 (hexane/EtOAc = 3/1); IR (NaCl, neat) νmax 3447, 2097, 1254, 701 cm-1; H NMR (500 MHz,
CDCl3) δ 7.47–7.45 (m, 2H), 7.34–7.31 (m, 2H), 7.24 (m, 1H), 6.19 (dd, 1H, J = 17.0, 10.0 Hz), 5.86 (td,
1H, J = 11.5, 2.0 Hz), 5.49 (dt, 1H, J = 11.5, 7.5 Hz), 5.34 (dd, 1H, J = 17.0, 1.0 Hz), 5.18 (dd, 1H, J =
10.0, 1.5 Hz), 3.11 (t, 2H, J = 6.5 Hz), 2.22–2.11 (m, 2H), 1.53 (tt, 2H, J = 7.5, 7.0 Hz); 13C NMR (126
MHz, CDCl3) δ 145.8, 143.5, 135.3, 132.0, 128.3, 127.2, 125.9, 112.6, 77.4, 50.7, 28.2, 25.2; HRMS (CI)
calcd for C14H18N3O [(M+H)+] 244.1450, found 244.1436.
6-(2-(3,4-Dimethoxyphenyl)-1H-inden-3-yl)-1-azabicyclo[3.1.0]hexane (26): To a stirred solution of
25 (18.6 mg, 0.049 mmol) in CH2Cl2 (0.5 mL) was added TMSOTf (18 μL, 0.1 mmol) at -78 °C. After 15
min, saturated ammonium chloride aqueous solution was added to stop the reaction. The mixture was
extracted with CH2Cl2 and was washed with brine. Collected organic layer was dried over Na2SO4, and
was concentrated in vacuo. The residue was purified by silica gel column chromatography
(hexane/EtOAc = 2/1 to 1/1) to afford 26 (5.5 mg, 34%). Pale yellow solid; Rf value 0.47 (hexane/EtOAc
= 1/1); mp 79.9–80.7 °C; IR (NaCl, neat) νmax 2958, 2935, 1515, 1461, 1262, 1244, 1026 cm-1; 1H NMR

(500 MHz, CDCl3) δ 7.69 (d, 1H, J = 7.5 Hz), 7.41 (d, 1H, J = 7.5 Hz), 7.29 (t, 1H, J = 7.0 Hz), 7.17 (t,
1H, J = 7.5 Hz), 7.09 (dd, 1H, J = 8.0, 2.0 Hz), 7.05 (d, 1H, J = 1.5 Hz), 6.92 (d, 1H, J = 8.5 Hz), 3.94 (s,
3H), 3.93 (s, 3H), 3.82–3.59 (m, 2H), 3.28 (dd, 1H, J = 12.5, 8.0 Hz), 3.06 (dt, 1H, J = 11.5, 7.5 Hz), 2.58
(s, 1H), 2.54 (dd, 1H, J = 5.0, 3.0 Hz), 2.25 (dd, 1H, J = 13.0, 8.0 Hz), 2.02–1.94 (m, 1H), 1.76 (m, 1H),
1.63 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 148.4, 148.2, 145.8, 142.6, 142.1, 135.2, 129.7, 126.4,
124.4, 123.2, 121.0, 111.6, 110.8, 55.9, 55.8, 53.3, 46.9, 41.2, 34.7, 26.3, 20.5; HRMS (ESI) calcd for
C22H24NO2 [(M+H)+] 334.1807, found 334.1803.
ACKNOWLEDGEMENTS
This work was supported in part by the Sasakawa Scientific Research Grant from the Japan Science
Society Fellowship (25-303). We acknowledge the fellowship of the Japan Chemical Industry
Association, and the presidential special research support fellowship of NAIST for T.Y. We also thank
Ms. Yuriko Nishiyama, Ms. Yoshiko Nishikawa, Mr. Kazuo Fukuda (MS), and Mr. Shohei Katao (X-ray
analysis) of NAIST.
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